A high-fructose diet is linked to the epidemic of hypertension, diabetes, and obesity. Up to 25 million Americans consume up to 20% of their calories from added fructose1, 2. We found that feeding rats a fructose-enriched diet (20%) for 4 weeks did not increase blood pressure. However, a fructose-enriched diet combined with high salt (4% Na) caused salt-sensitive hypertension within 1 week (Figures 1, 11); prior to the development of metabolic abnormalities. The initial phase of salt-sensitive hypertension is in part mediated by a renal defect that prevents NaCl excretion during high salt intake. The thick ascending limb (TAL) reabsorbs 25% of filtered NaCl. Enhanced TAL NaCl absorption is related to salt-sensitive hypertension in humans and rodents3-5. However, the mechanism by which a fructose-enriched diet rapidly (1 week) causes salt-sensitive hypertension is not clear and the role of TAL NaCl absorption in this process is completely unknown. NaCl reabsorption by the TAL depends on the apical Na/K/2Cl cotransporter NKCC2, the target of loop diuretics. Our preliminary data show that a fructose-enriched diet enhanced NKCC2 phosphorylation at Threonine (Thr) 96,101. NKCC2 phosphorylation at Thr96, 101 activates NKCC26, 7. Our data show that NKCC2-mediated NaCl transport is abnormally elevated in rats fed fructose plus a high salt diet. However, the effects of fructose and the signaling induced in the TAL and the distal nephron have not been studied. Our data show that plasma and urine fructose increase rapidly after fructose intake. Thus, fructose reaching the nephron may be transported in by a fructose channel, activating protein kinase signaling. The only kinases known to phosphorylate Thr96, 101 of NKCC2 are SPAK (STE20/SPS1-related proline-alanine-rich kinase) and OSR1 (Oxidative Stress Responsive 1) kinases. In the TAL, these kinases specifically phosphorylate NKCC2. In the distal convoluted tubule (DCT), these kinases specifically phosphorylate the thiazide-sensitive NaCl transporter NCC. We found that a 20% fructose diet increases SPAK/OSR1 phosphorylation in TALs. In addition, stimulation of ?-adrenergic receptors (?-AR) in the TAL activates NKCC213. A fructose-enriched diet may increase sympathetic activity by 2 weeks12, or enhance the sensitivity or signaling of ?-AR. Our preliminary data show that ?-AR stimulation increases SPAK/OSR1 phosphorylation in TALs. In the Dahl salt sensitive (SS) rat, NKCC2 and SPAK/OSR1 phosphorylation are abnormally enhanced in a normal salt diet. It is not known whether this increases the effect of fructose on blood pressure and NaCl absorption. We hypothesize that a fructose-enriched diet enhances thick ascending limb (TAL) and distal tubule (DCT) NaCl absorption by inducing NKCC2 and NCC phosphorylation via SPAK/OSR1 kinases and enhanced ?-AR signaling. These effects occur within 1 week, prior to metabolic alterations, and are maintained chronically (16 weeks), promoting salt-sensitive hypertension in normal rats. In Dahl SS rats, abnormally elevated SPAK/OSR1 in the TAL, enhances the effect of fructose on blood pressure in normal- or high-salt diets.